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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate the alternation of blood vessel relaxation in chronic renal failure (CRF) induced by adenine or partial-nephrectomy. The aorta was employed as the blood vessel material. CRF aorta relaxation in both adenine and partial nephrectomy induced rats increased when treated with glyceryl trinitrate (GTN). In the CRF animals, cGMP levels increased with the severity of CRF status. Aorta cytosolic glutathione S-transferase micro (GSTmicro) activity and enzyme contents increased with CRF. The effect of GTN on aortic vasorelaxation in both CRF statuses completely disappeared by the treatment with sodium nitoprusside. The effects of GTN were observed equally in both adenine- and partial nephrectomy-induced CRF rats. We concluded that alterations of aortic vasorelaxation by GTN in adenine- and partial nephrectomy-induced renal failure rats were caused by the enhancement of nitrogen monoxide production on the aortic blood vessel mediated by the induced GSTmicro in the aorta. This GSTmicro induction is peculiar to CRF since different CRF induction procedures produce the same results.
Res Commun Mol Pathol Pharmacol 1999
PMID:Enhancement of nitroglycerin induced blood vessel relaxation in chronic renal failure model rats. 1112 5

Recently, we have shown that erythrocytes obtained from patients with chronic renal failure (CRF) exhibited an increased rate of ATP formation from adenine as a substrate. Thus, we concluded that this process was in part responsible for the increase of adenine nucleotide concentration in uremic erythrocytes. There cannot be excluded however, that a decreased rate of adenylate degradation is an additional mechanism responsible for the elevated ATP concentration. To test this hypothesis, in this paper we compared the rate of adenine nucleotide breakdown in the erythrocytes obtained from patients with CRF and from healthy subjects. Using HPLC technique, we evaluated: (1) hypoxanthine production by uremic RBC incubated in incubation medium: (a) pH 7.4 containing 1.2 mM phosphate (which mimics physiological conditions) and (b) pH 7.1 containing 2.4 mM phosphate (which mimics uremic conditions); (2) adenine nucleotide degradation (IMP, inosine, adenosine, hypoxanthine production) by uremic RBC incubated in the presence of iodoacetate (glycolysis inhibitor) and EHNA (adenosine deaminase inhibitor). The erythrocytes of healthy volunteers served as control. The obtained results indicate that adenine nucleotide catabolism measured as a hypoxanthine formation was much faster in erythrocytes of patients with CRF than in the cells of healthy subjects. This phenomenon was observed both in the erythrocytes incubated at pH 7.4 in the medium containing 1.2 mM inorganic phosphate and in the medium which mimics hyperphosphatemia (2.4 mM) and metabolic acidosis (pH 7.1). The experiments with EHNA indicated that adenine nucleotide degradation proceeded via AMP-IMP-Inosine-Hypoxanthine pathway in erythrocytes of both patients with CRF and healthy subjects. Iodoacetate caused a several fold stimulation of adenylate breakdown. Under these conditions: (a) the rate of AMP catabolites (IMP + inosine + adenosine + hypoxanthine) formation was substantially higher in the erythrocytes from patients with CRF; (b) in erythrocytes of healthy subjects degradation of AMP proceeded via IMP and via adenosine essentially at the same rate; (c) in erythrocytes of patients with CRF the rate of AMP degradation via IMP was about 2 fold greater than via adenosine. The results presented in this paper suggest that adenine nucleotide degradation is markedly accelerated in erythrocytes of patients with CRF.
Mol Cell Biochem 2000 Oct
PMID:Accelerated degradation of adenine nucleotide in erythrocytes of patients with chronic renal failure. 1112 63

The contribution of cardiovascular activity in the early central responses to systemic inflammation was assessed in rats following intravenous administration of subseptic doses of lipopolysaccharide (LPS). LPS at 12.5 microg/kg increased heart rate (HR) but did not alter mean arterial pressure (MAP), and induced interleukin-1 beta (IL-1 beta) gene expression at 1 h in circumventricular organs (CVOs), choroid plexus, meninges, blood vessels, and pituitary gland. IL-1 beta mRNA levels were attenuated at 2 h in most regions studied. LPS at 50 microg/kg caused a biphasic change in MAP, increased HR, increased levels of arginine vasopressin heteronuclear RNA in the hypothalamic paraventricular nucleus (PVN), and induced IL-1 beta gene expression in the nucleus of the solitary tract (NTS) at 1 h. LPS (both doses) induced Fos-like immunoreactivity (FLI) in the area postrema, organum vasculosum of the lamina terminalis, NTS, preoptic area, supraoptic nucleus, and PVN at 1 h. In the PVN, neurons with FLI were found primarily in the dorsal and dorsal medial parvocellular divisions after 12.5 microg/kg of LPS whereas neurons with FLI were found throughout the PVN after 50 microg/kg of LPS. After 2 h, FLI was widespread throughout the brain. Plasma ACTH levels were elevated at 1 and 2 h in response to both doses of LPS, and levels of CRF mRNA were increased after 2 h in the parvocellular PVN. Our results reveal that central responses to increasing doses of LPS show different patterns which are related to activation of distinct immune and viscerosensory pathways, and that cardiovascular responses contribute to early neuronal activation as LPS concentrations are increased.
Brain Res Mol Brain Res 2001 Apr 18
PMID:Cardiovascular responses to subseptic doses of endotoxin contribute to differential neuronal activation in rat brain. 1131 77

Nitric oxide (NO)-dependent soluble guanylyl cyclase (sGC) is operative in mammalian cells, but its presence and the role in cGMP production in pituitary cells have been incompletely characterized. Here we show that sGC is expressed in pituitary tissue and dispersed cells, enriched lactotrophs and somatotrophs, and GH(3) immortalized cells, and that this enzyme is exclusively responsible for cGMP production in unstimulated cells. Basal sGC activity was partially dependent on voltage-gated calcium influx, and both calcium-sensitive NO synthases (NOS), neuronal and endothelial, were expressed in pituitary tissue and mixed cells, enriched lactotrophs and somatotrophs, and GH(3) cells. Calcium-independent inducible NOS was transiently expressed in cultured lactotrophs and somatotrophs after the dispersion of cells, but not in GH(3) cells and pituitary tissue. This enzyme participated in the control of basal sGC activity in cultured pituitary cells. The overexpression of inducible NOS by lipopolysaccharide + interferon-gamma further increased NO and cGMP levels, and the majority of de novo produced cGMP was rapidly released. Addition of an NO donor to perifused pituitary cells also led to a rapid cGMP release. Calcium-mobilizing agonists TRH and GnRH slightly increased basal cGMP production, but only when added in high concentrations. In contrast, adenylyl cyclase agonists GHRH and CRF induced a robust increase in cGMP production, with EC(50)s in the physiological concentration range. As in cells overexpressing inducible NOS, the stimulatory action of GHRH and CRF was preserved in cells bathed in calcium-deficient medium, but was not associated with a measurable increase in NO production. These results indicate that sGC is present in secretory anterior pituitary cells and is regulated in an NO-dependent manner through constitutively expressed neuronal and endothelial NOS and transiently expressed inducible NOS, as well as independently of NO by adenylyl cyclase coupled-receptors.
Mol Endocrinol 2001 Jun
PMID:Spontaneous and receptor-controlled soluble guanylyl cyclase activity in anterior pituitary cells. 1137 18

The effect of over-expressing neuronal calcium sensor 1 (NCS-1) upon stimulated adrenocorticotrophin (ACTH) secretion was studied in AtT-20 cells. Stably-transfected AtT-20 cell lines over-expressing NCS-1 were obtained and compared to wild type AtT-20 cells. Corticotrophin releasing factor (CRF-41)-stimulated ACTH secretion from NCS-1 over-expressing cells was significantly reduced from that obtained in wild type AtT-20 cells. The effects of other stimulants of ACTH secretion from wild type AtT-20 cells were not attenuated in NCS-1 over-expressing cells. Calcium, guanosine 5'-O-(3'-thiotriphosphate) (GTP-gamma-S) and mastoparan stimulated ACTH secretion from permeabilised wild type AtT-20 and NCS-1 over-expressing AtT-20 cells with significantly greater ACTH secretion obtained in NCS-1 over-expressing cells. This study shows that in intact cells over-expression of NCS-1 reduces exocytotic ACTH release, while in permeabilised cells increases ACTH release. NCS-1 has multiple cellular targets and that directly and indirectly via these targets acts to increase the releasable ACTH pool while inhibiting CRF-41 stimulus-secretion coupling.
Mol Cell Endocrinol 2001 Nov 26
PMID:Over-expression of NCS-1 in AtT-20 cells affects ACTH secretion and storage. 1169 41

Changes in lipid metabolism are an important risk factor for vascular complications during chronic renal failure (CRF). In experimental CRF hypercholesterolemia has been found to be the main lipid disorder. It is probably due to enhanced cholesterologenesis. Mechanisms of these changes remain poorly understood. It is well known that activity of cholesterologenesis undergoes a significant diurnal rhythm. However, there was no evidence that this rhythm is still present in the course of experimental CRF. Results of our studies indicate that in contrast to puromycin induced nephrotic syndrome, diurnal rhythm of cholesterologenesis in CRF rats is preserved both in liver and in the intestine tissue. Significant higher incorporation of tritiated water into cholesterol fraction was found in vivo both in liver as well as in intestine of CRF rats, as compared to control animals. Increased (with comparison to the controls) incorporation of 14C-acetate, and 3H-mevalonate into CRF rat liver sterols indicate that mechanism of enhanced cholesterologenesis is more complex than simply due to the elevated level of mevalonate (potential substrate for cholesterologenesis) which has been reported in plasma of CRF animals.
Mol Cell Biochem 2001 Dec
PMID:Diurnal rhythm of cholesterol biosynthesis in experimental chronic renal failure. 1185 39

Intracellular catabolism of NAD in mammalian cells occurs mainly via reaction catalyzed by poly(ADP-ribose) polymerase (PARP) with the release of nicotinamide, which is then metabolized predominantly to N-methyl-2-pyridone-5-carboxamide (2PY). PARP could be activated by binding to broken DNA and is known to be involved in DNA repair mechanisms, cell stress response and regulation of apoptosis. 2PY may accumulate under disease conditions resulting in accelerated DNA damage and retention of catabolic products. Our hypothesis was that chronic renal failure would lead to elevation of 2PY and potentially to inhibition of PARP and related physiological mechanisms. In the present study we: (a) compared plasma 2PY concentration in healthy subjects and in patients with chronic renal failure (CRF); (b) evaluated the relationship between plasma 2PY concentration and the severity of CRF; (c) evaluated the effect of hemodialysis treatment and kidney transplantation on 2PY concentration. We found that the plasma 2PY concentration in healthy subjects is 0.83+/-0.18 microM but it could increase up to 40 microM in patients with CRF. A significant correlation was found in CRF between plasma 2PY and creatinine concentration. A single hemodialysis treatment was associated with significant reduction of plasma 2PY concentration after the hemodialysis, but it increased rapidly 48 h after the end of treatment. Successful kidney transplantation was associated with return of 2PY concentration to the normal range. In conclusion, our results indicated significant production of 2PY in humans. In healthy subjects 2PY is cleared from the plasma by excretion in the urine. Altered excretion by the kidney leads to increase in plasma concentration of 2PY. It is possible that 2PY may play a significant role in the development of uremic toxemia, especially as an inhibitor of poly(ADP-ribose)polymerase.
Mol Cell Biochem 2002 Feb
PMID:Accumulation of plasma N-methyl-2-pyridone-5-carboxamide in patients with chronic renal failure. 1195 69

The ligand selectivity of human (hCRF(2A)) and Xenopus laevis (xCRF(2)) forms of the corticotropin-releasing factor type 2 (CRF(2)) receptor differs. The purpose of this study was to identify amino acids in these two CRF(2) receptors conferring these differences. An amino acid triplet in the third extracellular domain (Asp(262)Leu(263)Val(264) in hCRF(2A) or Lys(264)Tyr(265)Ile(266) in xCRF(2)) was found to diverge between both receptors. When binding and signaling characteristics of receptor mutants hR2KYI and xR2DLV were assessed, the tri-amino acid motif replacement produced receptors with binding properties resembling the xCRF(2) receptor. The converse mutation created a mutant receptor with a binding pharmacology identical to the profile of the hCRF(2A) receptor. This effect was most notable for xR2DLV, which possessed a binding affinity for astressin approximately 15-fold greater for astressin than sauvagine. In contrast, the binding profiles of the hCRF(2A) receptor and hR2KYI did not differ. These data indicate that another domain of the xCRF(2) receptor mediated low-affinity binding of astressin. Two amino acids in the first extracellular domain differ in xCRF(2) (Asp(69)Ser(70)) and hCRF(2A) (Glu(66)Tyr(67)) receptors. The hCRF(2A) receptor mutant (hR2DS-KYI) bound astressin with a low affinity indistinguishable from the xCRF(2) receptor. Therefore, these data demonstrate that ligand selectivity differences between amphibian and human forms of the CRF(2A) receptor are governed by these two motifs of the extracellular domains of the xCRF(2) receptor.
Mol Pharmacol 2002 May
PMID:Five amino acids of the Xenopus laevis CRF (corticotropin-releasing factor) type 2 receptor mediate differential binding of CRF ligands in comparison with its human counterpart. 1196 Nov 31

XLalpha(s), the large variant of the stimulatory G protein alpha subunit (Gsalpha), is derived from GNAS1 through the use of an alternative first exon and promoter. Gs(alpha) and XLalpha(s) have distinct amino-terminal domains, but are identical over the carboxyl-terminal portion encoded by exons 2-13. XLalpha(s) can mimic some functions of Gs(alpha), including betagamma interaction and adenylyl cyclase stimulation. However, previous attempts to demonstrate coupling of XLalpha(s) to typically Gs-coupled receptors have not been successful. We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XLalpha(s) and Gs(alpha) (Gnas(E2-/E2-)). Gnas(E2-/E2-) cells transfected with plasmids encoding XLalpha(s) and different heptahelical receptors, including the beta2-adrenergic receptor and receptors for PTH, TSH, and CRF, showed agonist-mediated cAMP accumulation that was indistinguishable from that observed with cells transiently coexpressing Gs(alpha) and these receptors. Our findings thus indicate that XLalpha(s) is capable of functionally coupling to receptors that normally act via Gs(alpha).
Mol Endocrinol 2002 Aug
PMID:Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit. 1214 44

Mechanisms of nonpeptide ligand action at family B G protein-coupled receptors are largely unexplored. Here, we evaluated corticotropin-releasing factor 1 (CRF(1)) receptor regulation by nonpeptide antagonists. The antagonist mechanism was investigated at the G protein-coupled (RG) and uncoupled (R) states of the receptor in membranes from Ltk(-) cells expressing the cloned human CRF(1) receptor. R was detected with the antagonist (125)I-astressin with 30 microM guanosine 5'-O-(3-thiotriphosphate present, and RG detected using (125)I-sauvagine. At the R state, nonpeptide antagonists antalarmin, NBI 27914, NBI 35965, and DMP-696 only partially inhibited (125)I-astressin binding (22-32% maximal inhibition). NBI 35965 accelerated (125)I-astressin dissociation and only partially increased the IC(50) value of unlabeled sauvagine, CRF, and urocortin for displacing (125)I-astressin binding (by 4.0-7.1-fold). Reciprocal effects at the R state were demonstrated using [(3)H]NBI 35965: agonist peptides only partially inhibited binding (by 13-40%) and accelerated [(3)H]NBI 35965 dissociation. These data are quantitatively consistent with nonpeptide antagonist and peptide ligand binding spatially distinct sites, with mutual, weak negative cooperativity (allosteric inhibition) between their binding. At the RG state the compounds near fully inhibited (125)I-sauvagine binding at low radioligand concentrations (79-94 pM). NBI 35965 did not completely inhibit (125)I-sauvagine binding at high radioligand concentrations (82 +/- 1%, 1.3-2.1 nM) and slowed dissociation of (125)I-sauvagine and (125)I-CRF. The antagonist effect at RG is consistent with either strong allosteric inhibition or competitive inhibition at one of the peptide agonist binding sites. These findings demonstrate a novel effect of R-G interaction on the inhibitory activity of nonpeptide antagonists: Although the compounds are weak inhibitors of peptide binding to the R state, they strongly inhibit peptide agonist binding to RG. Strong inhibition at RG explains the antagonist properties of the compounds.
Mol Pharmacol 2003 Mar
PMID:Mechanism of corticotropin-releasing factor type I receptor regulation by nonpeptide antagonists. 1260 86


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